The liver is the major metabolic control organ of the human body that comprises thousands of minute lobules (lobuli hepatis), the functional units of the organ. Liver tissue contains two major differentiated cell types: parenchymal cells (i.e., hepatocytes) and non-parenchymal cells. The complex functions of liver are exerted to a large extent by hepatocytes, whereas non-parenchymal cells such as Kupffer cells, Ito cells and liver sinusoidal endothelial cells (LSEC) play important roles in supporting and providing supplies to hepatocytes. The liver acts as a guardian interposed between the digestive tract and the rest of the body. A major hepatic function involves effective uptake, storage, metabolism and distribution to blood and bile large amounts of substances such as carbohydrates, lipids, amino acids, vitamins and trace elements. Another function of the liver is the detoxification of xenobiotic pollutants, drugs and endogenous metabolites, through both phase I (oxidation/reduction) and phase II (conjugation) mechanisms. Because of its essential role to life, liver dysfunction and diseases are often debilitating and life threatening. A number of acute or chronic pathological conditions are associated with structural and/or functional abnormalities of the liver. These include, but are not limited to, liver failure, hepatitis (acute or chronic), liver cirrhosis, toxic liver damage (for example alcohol), medicamentary liver damage, hepatic encephalopathy, hepatic coma and hepatic necrosis. Many chemical and biological agents, either therapeutic or purely harmful, can induce liver damages and thus are hepatotoxic. Liver cirrhosis results from the healing of a liver injury caused by viral or autoimmune hepatitis, alcohol abuse or other causes of liver damage. In liver cirrhosis, the scar tissue blocks the flow of blood through the liver and consequently this results in an increase in the pressure within the portal vein (the vein that carries the blood from the digestive organs to the liver) which is designated as portal hypertension. Increased pressure in the portal vein causes large veins (varices) to develop across the esophagus and stomach to bypass the blockage. The pressure in the varices increases and may rupture. Portal hypertension may also be caused by thrombosis, or clotting in the portal vein. Portal hypertension (PHT) in humans and laboratory animals is associated with a hyperkinetic circulation, vasodilation in the splanchnic territory and an hypersplenism. The hypersplenism can lead to an important pancytopenia.
Splanchnic vasodilation, the well-known increase in blood flow through the splanchnic organs draining into the portal venous system, is a major contributing factor for maintenance and aggravation of portal hypertension. The mechanisms by which portal hypertension induces this splanchnic vasodilation are not completely understood. Many theories have been proposed including an increase in circulating levels of vasodilator substances and reduced sensitivity to vasoconstrictors. Nevertheless, there is experimental evidence that splanchnic vasodilation in portal hypertension can be partially caused or maintained by structural vascular changes. In the venous circulation related to portal hypertension, portosystemic collaterals are formed which cause shunting of blood from the portal to the systemic circulation. Despite these collaterals, portal hypertension remains present. It has been shown recently that the formation of collateral vessels can be markedly inhibited by blockade of the vascular endothelial growth factor (VEGF) signalling pathway (Fernandez M et al Gastroenterology 2004; 126: 886-894). Our own experimental studies by intravital microscopy revealed also an increased angiogenesis in the peritoneal microcirculation of rats with PHT and cirrhosis. Evidence also shows that angiogenesis plays an important role in the development of liver fibrosis (Yoshiji H et al, Gut 2003: 52: 1347-1354; Lai W K et al, J Hepatol 2005; 42: 7-11; Medina J et al J Hepatol 2005; 42: 124-131). It has been shown that VEGF expression significantly increases during the development of liver fibrosis in experimental studies (Corpechot C et al, Hepatology 2002; 35:1010-21). Although recently an important role for placental growth factor (PIGF) has been described in pathological angiogenesis (patent application WO0185796, it is described that the use of VEGF-Receptor 1 agonists (such as PIGF) has a positive role for the treatment of cirrhosis (see patent application WO03103581, from Genentech, Inc.). The present invention surprisingly indicates the reverse and shows that molecules that can prevent the interaction between PIGF and its receptor, VEGF-R1 can be used for the manufacture of a medicament to treat cirrhosis and its complications such as portal hypertension and splanchnic vasodilatation.